Method and disposable device for sampling and distributing a liquid, for example, in sterile conditions

ABSTRACT

The invention relates to a method of distributing a fluid. According to the invention, the following elements are connected simultaneously to a valve ( 1 ) which comprises multiple inlets and outlets and which is equipped with a check valve, namely: a fluid sampling and injecting device, such as a syringe ( 2 ); a gas (e.g. air) supply conduit; a supply conduit for the liquid to be distributed; and a discharge conduit ( 6 ). The inventive method consists in: drawing in the liquid to be distributed in order to transfer same to the sampling and injecting device ( 2 ), injecting the liquid into the discharge conduit ( 6 ), drawing in the gas in order to transfer same to the sampling and injecting device ( 2 ), and injecting the gas into the discharge conduit ( 6 ) in order to push the remaining liquid into the discharge conduit ( 6 ). The invention also relates to a device and kit for implementing said method.

The present invention relates to a method and disposable device forsampling and apportionment of liquid, in particular under sterileconditions.

In the fields in particular of food, medicine, pharmaceuticals orbiotechnology, there is the problem of the repeated transfer of fluidsin particular in a sterile manner, and apportionment of a reproducible,precisely measured volume.

Today, this type of operation is carried out by separate, successiveactions which multiply the connection/disconnection operations. Themultiplication of these connections/disconnections leads to a high riskof contamination, either by exposure to the air, or because of incorrecthandling by the operator.

A standard application is, for example in parenteral nutrition, thepreparation of batches of nutritive mixtures to be administeredsubsequently to the patient, from a certain number of stock solutionssuch as: a solution of amino acids, a glucose solution, a lipidemulsion, to which are added small volumes of complementary substratessuch as trace elements, mineral salts and vitamins.

In paediatrics and neonatology in particular, the composition of thesemixtures is varied from day to day as a function of the nutritive stateof the patient and the need to ensure that he has a suitable calorieintake.

The need to vary this mixture from day to day does not allow the use ofstandard mixtures supplied by the pharmaceuticals industry, thecomposition of which does not vary by definition.

These mixtures must therefore be prepared in the hospital, underperfectly aseptic conditions. This operation is generally carried out ona laboratory table under a laminar air flow.

A standard application is, for example in biotechnology, the repeatedtaking of samples from a solution in cell culture, throughout this sameculture which extends over several days. This repeated sampling makes itpossible to ensure counting of the cells in a given volume and thus tofollow their growth curve, and even to carry out sterility tests on thesamples taken in order to ensure the absence of any contamination.

According to the method stage, this operation is generally carried outeither on a laboratory table, or under a laminar air flow, or incontrolled production zone.

In cell therapy, cells potentialized by genetic engineering have to beapportioned and then cultured in multiple reproducible individual doses,for subsequent administration to the patient (autologous vaccine).

This apportionment requires the reproducibility of each of the doses andthe transfer of the latter in sterile mode. This operation is generallycarried out on a laboratory table, under a laminar air flow.

It would therefore be desirable to have a simple method which is easy toimplement, for distribution and apportionment of a fluid, in particularunder sterile conditions.

After prolonged research the Applicant has developed such a method.

This is why a subject of the present Application is a method fordistribution of a fluid characterized in that

-   a) there are connected simultaneously to a multiple inlet and outlet    valve equipped with a non-return valve    -   a fluid sampling and injection device such as a syringe,    -   an inlet pipe for gas such as air,    -   an inlet pipe for liquid to be distributed    -   an outlet pipe preferably equipped with a branch towards a waste        container,-   b) the liquid to be distributed is drawn off in order to be    transferred into the sampling and injection device,-   c) it is injected into the outlet pipe,-   d) gas is drawn off in order to be transferred into the sampling and    injection device,-   e) the gas is injected into the outlet pipe in order to push the    liquid remaining in the outlet pipe.

The multiple inlet and outlet valve equipped with a non-return valve isarranged in order to let in the liquid to be distributed, to let it outtowards the sampling and injection device, to let it in from thesampling and injection device without the possibility of apportionmentby the entry of the liquid to be distributed (effect of the non-returnvalve), to let it out towards the outlet pipe. Such non-return valvesare well known. For example the valves marketed by the company FiltertekInc (USA) under the name 3-way check valve can be mentioned.

The inlet pipe of liquid to be distributed is connected to a containercontaining said liquid to be distributed. This container can be forexample a bottle or a pouch. This liquid inlet pipe is preferablyequipped with a valve allowing or not allowing communication between thecontainer and said inlet.

Under preferential conditions for implementing the invention, the inletpipe for liquid to be distributed is connected to several containerscontaining several liquids to be distributed and preferably to acontainer containing a rinsing liquid.

To this end, said liquid inlet pipe can be supplied by several supplytubes, each preferably being equipped with a valve.

The gas inlet pipe can open directly into the multiple inlet and outletvalve.

Under preferential conditions for implementing the invention, the gasoriginates from a branch pipe provided on the liquid inlet pipe. Thisbranch pipe is itself also preferably equipped with a valve allowing ornot allowing communication between the air intake and the liquid inletpipe.

Under other preferential conditions for implementing the invention, afilter, preferably a sterilizing filter is provided on the gas inletpipe. The gas, for example the nitrogen or air coming from this pipe, istherefore sterile.

The fluid sampling and injection device can for example be a pump inparticular a dosing pump, but is preferably a syringe.

The outlet pipe opens into a collecting container such as a flexiblepouch and preferably into several collecting containers. To this end,said outlet pipe can be separated into several tubes, each beingpreferably equipped with a valve.

The collecting container is advantageously pre-connected, i.e. thecontainer comprises connections allowing the direct mounting of saidcollecting container onto the outlet pipe(s).

A fraction of a single liquid to be distributed or a mixture of severalfractions of different liquids can be collected.

This outlet pipe is preferably equipped with a branch leading to a wastecontainer, equipped with a valve. In particular a rinsing fluid can thusbe eliminated.

Under yet other preferential conditions for implementing the invention,the multiple inlet and outlet valve is equipped with a pipe for arinsing liquid.

However, the rinsing liquid can be contained in one of the containers ofliquid to be distributed. This avoids the use of an additional inlet onthe multiple inlet and outlet valve.

Under yet other preferential conditions for implementing the methoddescribed above, the multiple inlet valve is connected by a pipe to arinsing liquid, a rinsing liquid is drawn off in order to be transferredinto the sampling and injection device, and it is injected into theoutlet pipe in order to be transferred towards a waste-recoverycontainer.

Under further other preferential conditions for implementing the methoddescribed above, the inlet pipe for liquid to be distributed is suppliedfor example by 1, 2, preferably 3 and particularly 4 containers ofliquid to be distributed or more.

The outlet pipe opens for example into 1, 2, preferably 3 andparticularly 4 or more collecting containers of the liquid or liquidsdistributed.

Apart from the multiple inlet and outlet valve, the other valves thefunction of which is to direct the flows of liquid and gas during theimplementation of the method can for example be taps or preferablyreversible clamps.

Under further other preferential conditions for implementing theinvention, the above liquid sampling and apportionment method isimplemented under sterile conditions, particularly using disposablecomponents.

A subject of the present Application is also a device which can be usedin an above method for distribution of a fluid characterized in that itcomprises a multiple inlet and outlet valve equipped with a non-returnvalve, said inlet and outlet valve being provided

-   -   with an adapter for receiving the fluid sampling and injection        device such as a syringe (Luer-lock® type for example),    -   with an inlet pipe for gas (for example air),    -   with an inlet pipe for liquid to be distributed    -   with an outlet pipe preferably equipped with a branch leading to        a waste container,

Under preferential conditions for implementing the invention, the aboveinlet pipe for liquid to be distributed moreover includes an adaptationsystem for cooperating with a container containing a liquid to bedistributed. This adaptation system can be perforating,self-perforating, be screw or bayonet fitting, have aseptic connectionsetc.

Under other preferential conditions for implementing the invention, thegas inlet pipe is a branch from the inlet pipe for liquid to bedistributed.

Under further other preferential conditions for implementing theinvention, the inlet pipe for liquid to be distributed comprises ashared section on the side of the multiple inlet and outlet valve andmoreover a set of tubes for several containers containing a liquid to bedistributed.

The gas inlet pipe is preferably connected onto the shared section ofthe inlet pipe for liquid to be distributed.

Under yet other preferential conditions for implementing the invention,the outlet pipe comprises a shared section on the side of the multipleinlet and outlet valve and moreover a set of tubes for severalcontainers having to contain a liquid to be distributed.

The pipe towards the waste container is preferably connected onto theshared section of the outlet pipe.

In the case of a single stock solution, the inlet pipe is also thesupply tube, advantageously in a single piece.

The method for distributing a fluid, which is the subject of the presentinvention has very useful qualities. In its version made from plastic,which is sterile and disposable:

-   -   it minimizes the number of connections under aseptic conditions        and therefore reduces the risk of contamination by contact with        the operator;    -   it implements the concept of the closed system, independent of        the ambient air and therefore reduces the risk of bacterial        contamination;    -   it is disposable, thus eliminating any risk of        cross-contamination, batch by batch;    -   it allows the precise measurement of the volume sampled or        transferred;    -   it allows the reproducibility of the volume transferred.

These qualities justify the use of the method for distributing a fluiddescribed above, in the applications referred to above.

The preferential conditions for implementing the methods described abovealso apply to the other subjects of the invention referred to above, inparticular to the devices for their implementation.

The invention will be better understood with reference to the attacheddrawing (FIG. 1) which is a diagrammatic representation of an example ofan assembly of the invention with multiple inlets and outlets.

In FIG. 1 it is possible to discern the central element of the methodand device according to the invention, a valve 1 with multiple inletsand outlets equipped with a non-return valve. This non-return valveallows the introduction of the liquid drawn off into the rigid body of asyringe 2 and its transfer, without returning downstream, towards theapportionment line.

It is then possible to discern from upstream to downstream in thecirculation of the liquids:

-   1) Upstream, an inlet line with multiple tubes 3 provided for    connecting to flasks, one or more pouches, a reactor or a tank,    containing the stock solution or solutions to be filled (not    represented). They join together into an inlet pipe 4 in the valve 1    with multiple inlets and outlets, and constitute a shared section.-   2) The valve 1 with multiple inlets and outlets.-   3) The syringe 2—which may or may not be pre-connected—with a    capacity for example of 10 ml to 500 ml allowing the precise    measurement (with a tolerance close to the measurement on the    syringe body) of the volume drawn off.-   4) Downstream, a distribution line with multiple tubes 5 allows the    transfer and apportionment of the fluid drawn off towards the    collecting pouches. They join together into an outlet pipe 6 of the    valve 1 with multiple inlets and outlets, which constitutes a shared    section.-   5) One or more collecting pouches 7 pre-connected or not    pre-connected to the distribution line, allowing the collection of    the volumes of stock solutions transferred.-   6) On the inlet line, upstream, a sterilizing hydrophobic filter 8    is pre-connected in a branch. Its function is to allow the    introduction of filtered air into the device and to evacuate all of    the dead volume of liquid which could remain there. The dead volume    of this closed system being constant, purging it makes it possible    to reproduce the drawing-off and transfer operation as many times as    desired, in reproducible manner.-   7) On the distribution line, downstream, a waste pouch 9    pre-connected to a branch, with a volume for example of 1 to 5    litres, makes it possible to collect either air, or part of the    liquid transferred serving as rinsing liquid between each transfer,    if necessary.-   8) Reversible sealing clamps. On all the branches of the device, a    reversible sealing clamp 10 is installed wherever necessary in order    to direct the flow of liquid or air during use (10S means that the    clamp is installed on an outlet tube, 10E that the clamp is    installed on an inlet tube, 10F that the clamp is installed on the    filter tube and 10R that the clamp is installed on the waste pouch    tube).

The above device can be used according to the following method:

-   1) The clamp on the desired inlet line is opened, the desired volume    of stock solution is drawn off by aspiration into the syringe 2,    measuring this volume on the body of the syringe.-   2) The clamp 10E on the inlet line is closed, the clamp 10S on the    apportionment line is opened, the measured volume of stock solution    is transferred into the apportionment line as far as the collection    pouch 7.-   3) The clamp 10E on the inlet line is closed, the clamp 10F    downstream of the hydrophobic filter 8 is opened, air is drawn    through the filter 8, using the syringe 2.-   4) The stock solution trapped in the dead volume is pushed by means    of the filtered air introduced up to the apportionment line is    emptied into the collection pouch 7.-   5) The clamp 10E on the inlet line is opened, a volume of stock    solution is drawn into the syringe 2.-   6) The clamp on the distribution line is closed, the clamp 10R of    the waste pouch is opened, the volume of stock solution is    transferred into the waste pouch 9, in order to rinse the pipes.

The above sequence is recommenced as many times as necessary in order toensure the repeated and reproducible transfer of the measured volume ofstock solution.

As may be understood by a person skilled in the art, a device such asthat above can be produced in modules from separate optionallymulti-purpose elements. In addition to the valve 1 with multiple inletsand outlets, pipes can be found which are equally suitable for the inletand the outlet, branched or not branched. For example the same type ofbranched pipes is equally suitable for mounting the filter and the wastepouch. Moreover a pipe suitable for the inlet and the outlet can bemounted on a piece provided with a set of channels allowing the samenumber of tubes to be mounted.

This is why a subject of the present Application is a fluid distributionunit characterized in that it comprises

-   -   a multiple inlet and outlet valve equipped with a non-return        valve, said valve being equipped with a fluid sampling and        injection device such as a syringe or an adapter such as a cone        for attaching a syringe, and    -   two pipes, one being equipped with a branch (Y-shaped pipe), or        four pipes and a branch end piece (3 pipes connected onto a        branch end piece corresponding to a pipe equipped with a        branch).

1. Method for distribution of a fluid characterized in that a) there areconnected simultaneously to a multiple inlet and outlet valve (1)equipped with a non-return valve a fluid sampling and injection devicesuch as a syringe (2), an inlet pipe for gas such as air, an inlet pipefor liquid to be distributed an outlet pipe (6), b) the liquid to bedistributed is drawn off in order to be transferred into the samplingand injection device (2), c) it is injected into the outlet pipe (6), d)gas is drawn off in order to be transferred into the sampling andinjection device (2), e) the gas is injected into the outlet pipe (6) inorder to push the liquid remaining in the outlet pipe (6).
 2. A methodaccording to claim 1, characterized in that the inlet pipe (4) forliquid to be distributed is connected to several containers containingseveral liquids to be distributed.
 3. A method according to claim 1,characterized in that the inlet pipe (4) for liquid to be distributed isconnected to a container containing a rinsing liquid.
 4. A methodaccording to claim 1, characterized in that the liquid inlet pipe (4) issupplied by several supply tubes (3), each being equipped with a valve(10E).
 5. A method according to claim 1, characterized in that the gasoriginates from a branch pipe provided on the liquid inlet pipe (4). 6.A method according to claim 1, characterized in that a filter (8), forexample a sterilizing filter, is provided on the gas inlet pipe (4). 7.A method according to claim 1, characterized in that the fluid samplingand injection device (2) is a dosing pump or a syringe.
 8. A methodaccording to claim 1, characterized in that the outlet pipe (6) opensinto one or more collecting containers (7).
 9. A method according toclaim 1, characterized in that the outlet pipe (6) separates intoseveral tubes (5), each being equipped with a valve (10S).
 10. A methodaccording to claim 1, characterized in that the collecting container (7)is pre-connected (or the collecting containers).
 11. A method accordingto claim 1, characterized in that a mixture of several fractions ofdifferent liquids is collected.
 12. A method according to claim 1,characterized in that the outlet pipe (6) is equipped with a branchtowards a waste container (9), equipped with a valve (10R).
 13. A methodaccording to claim 1, characterized in that the multiple inlet valve (1)is connected by a pipe to a rinsing liquid, a rinsing liquid is drawnoff in order to be transferred into the sampling and injection device(2), and it is injected into the outlet pipe (6) in order to betransferred towards a waste-recovery container (9).
 14. A methodaccording to claim 1, characterized in that the inlet pipe (4) forliquid to be distributed is supplied by 3 containers for liquid to bedistributed or more.
 15. A method according to claim 1, characterized inthat the outlet pipe (6) opens into 3 collecting containers of theliquid or liquids distributed or more.
 16. A method according to claim1, characterized in that it is implemented under sterile conditions, forexample using disposable components.
 17. A device which can be used in amethod as defined in claim 1 characterized in that it comprises amultiple inlet and outlet valve (1) equipped with a non-return valve,said valve being provided with an adapter for receiving the fluidsampling and injection device such as a syringe (Luer-lock® type forexample), with an inlet pipe for gas (for example air), with an inletpipe (4) for liquid to be distributed with an outlet pipe (6).
 18. Adevice according to claim 17, characterized in that the outlet pipe (6)is equipped with a branch towards a waste container (9).
 19. A deviceaccording to claim 17, characterized in that the inlet pipe (4) forliquid to be distributed comprises an adaptation system for cooperatingwith a container containing a liquid to be distributed.
 20. A deviceaccording to claim 17, characterized in that the inlet pipe (4) forliquid to be distributed comprises a shared section on the side of themultiple inlet and outlet valve and a set of tubes (3) for severalcontainers containing a liquid to be distributed.
 21. A device accordingto claim 17, characterized in that the gas inlet pipe is connected ontothe shared section of the inlet pipe (4) for liquid to be distributed.22. A device according to claim 17, characterized in that the outletpipe (6) comprises a shared section on the side of the multiple inletand outlet valve and a set of tubes (5) for several containers having tocontain the liquid distributed.
 23. A fluid distribution unitcharacterized in that it comprises a multiple inlet and outlet valve (1)equipped with a non-return valve, said valve being equipped with a fluidsampling and injection device such as a syringe or an adapter such as acone for adapting a syringe, and two pipes (4,6), one being equippedwith a branch, or four pipes and a branch end piece.